In this study, we determined the effect of 24 different synthetic 4-benzylpiperidine carboxamides on the reuptake of serotonin, norepinephrine, and dopamine (DA), and characterized their structure–activity relationship. The compounds with a two-carbon linker inhibited DA reuptake with much higher potency than those with a three-carbon linker. Among the aromatic ring substituents, biphenyl and diphenyl groups played a critical role in determining the selectivity of the 4-benzylpiperidine carboxamides toward the serotonin transporter (SERT) and dopamine transporter (DAT), respectively. Compounds with a 2-naphthyl ring were found to exhibit a higher degree of inhibition on the norepinephrine transporter (NET) and SERT than those with a 1-naphthyl ring. A docking simulation using a triple reuptake inhibitor 8k and a serotoninorepinephrine reuptake inhibitor 7j showed that the regions spanning transmembrane domain (TM)1, TM3, and TM6 form the ligand binding pocket. The compound 8k bound tightly to the binding pocket of all three monoamine reuptake transporters; however, 7j showed poor docking with DAT. Co-expression of DAT with the dopamine D2 receptor (D2R) significantly inhibited DA-induced endocytosis of D2R probably by reuptaking DA into the cells. Pretreatment of the cells with 8f, which is one of the compounds with good inhibitory activity on DAT, blocked DAT-induced inhibition of D2R endocytosis. In summary, this study identified critical structural features contributing to the selectivity of a molecule for each of the monoamine transporters, critical residues on the compounds that bound to the transporters, and the functional role of a DA reuptake inhibitor in regulating D2R function.

In this study, we determined the effect of 24 different synthetic 4-benzylpiperidine carboxamides on the reuptake of serotonin, norepinephrine, and dopamine (DA), and characterized their structure–activity relationship. The compounds with a two-carbon linker inhibited DA reuptake with much higher potency than those with a three-carbon linker. Among the aromatic ring substituents, biphenyl and diphenyl groups played a critical role in determining the selectivity of the 4-benzylpiperidine carboxamides toward the serotonin transporter (SERT) and dopamine transporter (DAT), respectively. Compounds with a 2-naphthyl ring were found to exhibit a higher degree of inhibition on the norepinephrine transporter (NET) and SERT than those with a 1-naphthyl ring. A docking simulation using a triple reuptake inhibitor 8k and a serotoninorepinephrine reuptake inhibitor 7j showed that the regions spanning transmembrane domain (TM)1, TM3, and TM6 form the ligand binding pocket. The compound 8k bound tightly to the binding pocket of all three monoamine reuptake transporters; however, 7j showed poor docking with DAT. Co-expression of DAT with the dopamine D2 receptor (D2R) significantly inhibited DA-induced endocytosis of D2R probably by reuptaking DA into the cells. Pretreatment of the cells with 8f, which is one of the compounds with good inhibitory activity on DAT, blocked DAT-induced inhibition of D2R endocytosis. In summary, this study identified critical structural features contributing to the selectivity of a molecule for each of the monoamine transporters, critical residues on the compounds that bound to the transporters, and the functional role of a DA reuptake inhibitor in regulating D2R function.

Purpose: This study was aim to evaluate the patterns of failure according to radiotherapy (RT) target volume for cervical lymph nodes in metastases of unknown primary origin in head and neck region (HNMUO). Materials and Methods: Sixty-two patients with HNMUO between 1998 and 2016 were retrospectively reviewed. We analyzed the clinical outcomes and primary site failure depending on the radiation target volume. The target volume was classified according to whether the potential head and neck mucosal sites were included and whether the neck node was treated involved side only or bilaterally. Results: Potential mucosal site RT (mucosal RT) was done to 23 patients and 39 patients did not receive mucosal RT. Mucosal RT showed no significant effect on overall survival (OS) and locoregional recurrence (LRR). The location of primary site failure encountered during follow-up period was found to be unpredictable and 75% of patients with recurrence received successful salvage therapies. No significant differences in OS and LRR were found between patients treated to unilateral (n = 35) and bilateral neck irradiation (n = 21). Treatment of both necks resulted in significantly higher mucositis. Conclusions We found no advantages in OS and LRR of patients with HNMUO when mucosal sites and bilateral neck node were included in the radiation target volume.

PURPOSE: We first analyzed the prognostic power of albumin-to-alkaline phosphatase ratio (AAPR) before radical radiotherapy (RT) in non-metastatic nasopharyngeal carcinoma (NPC) patients. MATERIALS AND METHODS: The records of 170 patients with biopsy-proven, non-metastatic NPC treated by radical RT between 1998 and 2016 at our institution were retrospectively reviewed. Median follow-up duration was 50.6 months. All patients received intensity-modulated RT and cisplatin based chemotherapy before, during, or after RT. The major treatment of patients was based on concurrent chemoradiotherapy (92.4%). The AAPR was calculated by the last value of both albumin and alkaline phosphatase within 1 month immediately preceding RT. The optimal cut-off level of AAPR was determined by using Cutoff Finder, a web-based system. Propensity score matching (PSM) analysis was performed. RESULTS: The optimal cut-off level of AAPR was 0.4876. After PSM analysis of whole cohort, an AAPR was not related to survival outcomes. In PSM analysis for patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC), an AAPR ≥ 0.4876 was related to better overall survival (OS), progression-free survival (PFS), and locoregional relapse–free survival (LRRFS) (OS: hazard ratio [HR], 0.341; 95% confidence interval [CI], 0.144 to 0.805; p=0.014; PFS: HR, 0.416; 95% CI, 0.189 to 0.914; p=0.029; and LRRFS: HR, 0.243; 95% CI, 0.077 to 0.769; p=0.016, respectively). CONCLUSION: The AAPR, inexpensive and readily derived from a routine blood test, could be an independent prognostic factor for patients with LA-NPC. And it might help physicians determine treatment plans by identifying the patient's current status. Future prospective clinical trials to validate its prognostic value are needed.
Alkaline Phosphatase ; Chemoradiotherapy ; Cisplatin ; Cohort Studies ; Disease-Free Survival ; Drug Therapy ; Follow-Up Studies ; Hematologic Tests ; Humans ; Prognosis ; Propensity Score ; Prospective Studies ; Radiotherapy ; Retrospective Studies

PURPOSE: Use of radiotherapy combined with chemotherapy is increasing in hypopharyngeal cancer. However, many show residual tumor after radiotherapy. Timing for treatment evaluation and salvage therapy is essential. However, optimal timing for salvage surgery has not been suggested. In this study, we tried to evaluate optimal timing for salvage surgery. METHODS AND MATERIALS: Patients who were diagnosed with hypopharyngeal squamous cell carcinoma between 2006 and 2015 were retrospectively analyzed. All patients received definitive radiotherapy with or without chemotherapy. Response of all treated patients were analyzed at 1, 3, and 6 months after radiotherapy. Any patients with progression before 6 months were excluded. RESULTS: A total of 54 patients were analyzed. Complete remission (CR) rates at 1 month (CR1), 3 months (CR3) and 6 months (CR6) were 66.7%, 81.5%, and 90.7%, respectively. Non-CR at 1 month (NCR1), 3 months (NCR3), and 6 months (NCR6) showed poor locoregional recurrence-free survival rates (1-year rates of 63.7%, 66.7%, and 0.0%, respectively) compared to CR1, CR3, and CR6 (1-year rates 94.3%, 88.0%, and 91.5%, respectively). Particularly significant differences were seen between CR6 and NCR6 (p < 0.001). Of 10 patients with NCR3, 5 showed CR at 6 months (NCR3/CR6). There was no statistical difference in locoregional recurrence-free survival between CR3 and NCR3/CR6 group (p = 0.990). CONCLUSION: Our data suggest half of patients who did not show CR at 3 months eventually achieved CR at 6 months. Waiting until 6 months after radiotherapy may be appropriate for avoiding additional salvage therapy.
Carcinoma, Squamous Cell ; Drug Therapy ; Humans ; Hypopharyngeal Neoplasms ; Hypopharynx ; Neoplasm, Residual ; Radiotherapy ; Retrospective Studies ; Salvage Therapy ; Survival Rate

Multifocal acquired demyelinating sensory and motor neuropathy (MADSAM) is a peripheral neuropathy characterized by multifocal weakness and associated sensory impairment. MADSAM is associated with multifocal persistent conduction block and other signs of demyelination. The incidence of cranial nerve involvement in MADSAM was recently reported to be approximately 15%. However, reports of hypoglossal neuropathy occurring in MADSAM are rare. Unilateral hypoglossal neuropathy in MADSAM is usually misdiagnosed as motor neuron disease. We report a patient with MADSAM presenting with tongue hemiatrophy.
Cranial Nerves ; Demyelinating Diseases ; Diagnosis, Differential ; Humans ; Hypoglossal Nerve Diseases ; Incidence ; Motor Neuron Disease ; Motor Neurons ; Peripheral Nervous System Diseases ; Tongue

A cavernous angioma (CA) and a developmental venous anomaly may consist a mixed vascular malformation (MVM). Two bleeding foci were observed in a MVM of a man with epilepsy. The hemodynamic association between the two foci was not clear. An advance of neuroimaging may enhance the susceptibility of detection of MVMs. We should consider a MVM when a daughter bleeding focus occurs near the main bleeding focus associated with a CA.
Brain* ; Cerebral Hemorrhage ; Epilepsy ; Hemangioma, Cavernous ; Hemodynamics ; Hemorrhage* ; Neuroimaging ; Nuclear Family ; Vascular Malformations*

PURPOSE: Surgical excision is the definitive treatment for localized recurrence of papillary thyroid carcinoma. Reoperation for recurrence, however, is challenging and associated with increased operative times and complication rates. For safe and effective reoperation, ultrasound-guided charcoal tattooing localization can be used. The aim of this study was to investigate the feasibility and safety of the ultrasound-guided charcoal tattooing localization. METHODS: Between November 2012 and August 2013, ten patients underwent preoperative charcoal tattooing localization for twelve recurrent lesions. Patient demographics, pathologic features, and operation results were reviewed. RESULTS: The technical success rate of charcoal tattooing was 100%. Eight patients had one recurrent lesion, and two patients had double lesions. Among these 12 recurrent lesions, three (25%) were found in level II, four (33%) in level IV, four (33%) in level VI, and one (8%) was found in the thyroidectomy bed site. The mean size of lesions was 0.87 +/- 0.35 cm. Of these 10 patients, eight patients underwent selective lymph node dissection, one patient underwent modified radical neck dissection, and one patient underwent recurrent mass excision. Transient hypocalcemia developed in one patient, and no recurrent laryngeal nerve palsy occurred. There were no major complications related to the injection of the charcoal. The mean follow-up period after reoperation was 8.6 +/- 2.7 months; in the follow-up ultrasound, there were no remnant lesions in all patients. CONCLUSION: Preoperative ultrasound-guided charcoal tattooing localization for recurrent thyroid cancer appears to be a feasible and safe procedure for reoperation. Further evaluation is warranted in larger patients' cohorts.
Charcoal* ; Cohort Studies ; Demography ; Follow-Up Studies ; Humans ; Hypocalcemia ; Lymph Node Excision ; Neck Dissection ; Operative Time ; Recurrence ; Reoperation ; Tattooing* ; Thyroid Neoplasms* ; Thyroidectomy ; Ultrasonography ; Vocal Cord Paralysis

BACKGROUND: Impressive improvement of survival rate has been achieved in childhood acute lymphoblastic leukemia (ALL). In an effort to balance the risks and benefits of therapy, risk-stratified therapy has been adopted. The aim of this study was to evaluate treatment outcome of childhood ALL by risk stratification.METHODS: From 184 patients (age, <18 years) with ALL newly diagnosed at Chonnam National University Hospital and Chonnam National University Hwasun Hospital between 2000 and 2010, we retrospectively analyzed 157 patients. Patients with infant ALL, L3, Down syndrome, and those transferred to another hospital were excluded. Three risk groups were defined as standard risk (SR, n=88), high risk (HR, n=52) and very high risk (VHR, n=17).RESULTS: The 7-year overall survival and event-free survival (EFS) rates were 85.2+/-2.9% and 80.2+/-3.3%, respectively. The 7-year EFS rates were 86.5+/-3.9% for SR, 78.8+/-5.7% for HR and 52.9+/-12.1% for VHR (P<0.001). Relapse occurred in 17 patients, and the cumulative incidence of relapse at 7 years was not different according to risk groups (SR vs. HR vs. VHR=8.9% vs. 17.3% vs. 5.9%, P=0.171). Among relapsed patients, 11 underwent hematopoietic stem cell transplantation of whom 5 survive event-free with a median follow-up of 5.2 years. The cumulative incidence of non-relapse mortality was highest in VHR (SR vs. HR vs. VHR=4.6% vs. 3.8% vs. 47.2%, P<0.001).CONCLUSION: Although, the number of patients included in this study is relatively small, the survival rates of childhood ALL with current strategies are encouraging. Also, efforts should be focused to further improve survival in the VHR, especially to reduce non-relapse mortality.
Adolescent ; Child ; Disease-Free Survival ; Down Syndrome ; Follow-Up Studies ; Hematopoietic Stem Cell Transplantation ; Humans ; Incidence ; Infant ; Jeollanam-do ; Mortality ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; Recurrence ; Retrospective Studies ; Risk Assessment ; Survival Rate ; Treatment Outcome

BACKGROUND: Over the past several decades, there has been a rapid worldwide increase in the prevalence of papillary thyroid cancer (PTC) as well as a number of changes in the clinicopathological characteristics of this disease. BRAF(V600E), which is a mutation of the proto-oncogene BRAF, has become the most frequent genetic mutation associated with PTC, particularly in Korea. Thus, the present study investigated whether the prevalence of the BRAF(V600E) mutation has increased over the past two decades in the Korean population and whether various PTC-related clinicopathological characteristics have changed. METHODS: The present study included 2,624 patients who underwent a thyroidectomy for PTC during two preselected periods; 1995 to 2003 and 2009 to 2012. The BRAF(V600E) mutation status of each patient was confirmed using the polymerase chain reaction-restriction fragment length polymorphism method or by the direct sequencing of DNA. RESULTS: The prevalence of the BRAF(V600E) mutation in Korean PTC patients increased from 62.2% to 73.7% (P=0.001) over the last two decades. Additionally, there was a greater degree of extrathyroidal extension (ETE) and lymph node metastasis in 2009 to 2012 patients with the BRAF(V600E) mutation and a higher frequency of thyroiditis and follicular variant-PTC in 2009 to 2012 patients with wild-type BRAF. However, only the frequency of ETE was significantly higher in 1995 to 2003 patients with the BRAF(V600E) mutation (P=0.047). Long-term recurrence rates during a 10-year median follow-up did not differ based on BRAF(V600E) mutation status. CONCLUSION: The BRAF(V600E) mutation rate in Korean PTC patients has been persistently high (approximately 70%) over the past two decades and continues to increase. The present findings demonstrate that BRAF(V600E)-positive PTC was associated with more aggressive clinicopathological features, especially in patients who were recently diagnosed, suggesting that BRAF(V600E) mutation status may be a useful prognostic factor for PTC in patients recently diagnosed with this disease.
DNA ; Follow-Up Studies ; Humans ; Korea ; Lymph Nodes ; Mutation Rate ; Neoplasm Metastasis ; Prevalence ; Prognosis ; Proto-Oncogenes ; Recurrence ; Thyroid Gland ; Thyroid Neoplasms* ; Thyroidectomy ; Thyroiditis